Interaction Map Driven Cocrystallization of Ambrisentan: Structural and Biopharmaceutical Evaluation,Crystal Growth & Design

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Interaction Map Driven Cocrystallization of Ambrisentan: Structural and Biopharmaceutical Evaluation
Crystal Growth & Design ( IF 3.2 ) Pub Date : 2020-06-08 , DOI: 10.1021/acs.cgd.0c00427
Jamshed Haneef ₁ , Datta Markad ₂ , Renu Chadha ₃

Affiliation

The present work deals with the development of cocrystal of ambrisentan (AMT) to improve its biopharmaceutical profile. Full interaction maps (FIM) of AMT were explored to find out the potential sites for hydrogen bonding and prediction of supramolecular synthons. This information was further applied to the screening of amino acids as prospective coformers for cocrystallization of AMT. Mechanochemical reactions have resulted in two cocrystals with l-aspartic acid and glycylglycine (dipeptide). The crystal structural analysis revealed that the hydrogen-bonding pattern in the developed cocrystals corroborated well with the predicted supramolecular synthons. The developed cocrystals showed a remarkable improvement in solubility, intrinsic dissolution rate, and in vivo systemic absorption as compared to the parent drug. Complementarily, Hirshfeld surface maps together with crystal features established a good structural–performance correlation of the developed cocrystals. Thus, the systematic cocrystallization driven by structural informatics tools is valuable in the development of novel solid forms with improved biopharmaceutical attributes.

中文翻译：

Ambrisentan的相互作用图驱动共结晶：结构和生物制药评价

本工作涉及安布森坦（AMT）共晶体的开发，以改善其生物药物特性。探索了AMT的全相互作用图（FIM），以发现潜在的氢键结合位点和超分子合成子的预测。该信息进一步应用于筛选氨基酸，作为AMT共结晶的预期共形成物。机械化学反应产生了带有1-天冬氨酸和甘氨酰甘氨酸（二肽）的两个共晶体。晶体结构分析表明，发达的共晶体中的氢键模式与预测的超分子合成子得到了很好的证实。发达的共晶体显示出溶解度，固有溶解速率和体内显着改善与母体药物相比全身吸收。作为补充，赫希菲尔德表面图和晶体特征建立了发达的共晶体的良好的结构-性能相关性。因此，由结构信息学工具驱动的系统共结晶在开发具有改善的生物药物特性的新型固体形式方面很有价值。

更新日期：2020-07-01

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